SCYL2 Protects CA3 Pyramidal Neurons from Excitotoxicity during Functional Maturation of the Mouse Hippocampus

Neuronal death caused by excessive excitatory signaling, excitotoxicity, plays a central role in neurodegenerative disorders. The mechanisms regulating this process, however, are still incompletely understood. Here we show that the coated vesicle-associated kinase SCYL2/CVAK104 plays a critical role for the normal functioning of the nervous system and for suppressing excitotoxicity in the developing hippocampus. Targeted disruption of Scyl2 in mice caused perinatal lethality in the vast majority of newborn mice and severe sensory-motor deficits in mice that survived to adulthood. Consistent with a neurogenic origin of these phenotypes, neuron-specific deletion of Scyl2 also caused perinatal lethality in the majority of newborn mice and severe neurological defects in adult mice. The neurological deficits in these mice were associated with the degeneration of several neuronal populations, most notably CA3 pyramidal neurons of the hippocampus, which we analyzed in more detail. The loss of CA3 neurons occurred during the functional maturation of the hippocampus and was the result of a BAX-dependent apoptotic process. Excessive excitatory signaling was present at the onset of degeneration, and inhibition of excitatory signaling prevented the degeneration of CA3 neurons. Biochemical fractionation reveals that Scyl2-deficient mice have an altered composition of excitatory receptors at synapses. Our findings demonstrate an essential role for SCYL2 in regulating neuronal function and survival and suggest a role for SCYL2 in regulating excitatory signaling in the developing brain. Significance statement: Here we examine the in vivo function of SCYL2, an evolutionarily conserved and ubiquitously expressed protein pseudokinase thought to regulate protein trafficking along the secretory pathway, and demonstrate its importance for the normal functioning of the nervous system and for suppressing excitatory signaling in the developing brain. Together with recent studies demonstrating a role of SCYL1 in preventing motor neuron degeneration, our findings clearly establish the SCY1-like family of protein pseudokinases as key regulators of neuronal function and survival.